Functional LTCC-β2AR Complex Needs Caveolin-3 and Is Disrupted in Heart Failure.
Jose L Sanchez-Alonso1, Laura Fedele1, Jaël S Copier1
1National Heart and Lung Institute, Imperial College London, United Kingdom (J.L.S.-A., L.F., J.S.C., C.L., C.M., A.J., T.B., J.G.).
Circulation Research
|June 14, 2023
Summary
Beta-2 adrenergic receptors (β2ARs) form functional complexes with L-type Ca2+ channels (LTCCs) in cardiomyocytes, but this coupling is lost in heart failure. This study reveals β2AR-LTCC proximity signaling is crucial for healthy heart function.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Beta-2 adrenergic receptors (β2ARs), but not beta-1 adrenergic receptors (β1ARs), form functional complexes with L-type Ca2+ channels (LTCCs) on cardiomyocyte membranes.
- The impact of microdomain localization on the function of these βAR-LTCC complexes remains largely unknown.
- Understanding these interactions is crucial for investigating disruptions in heart failure.
Purpose of the Study:
- To investigate the coupling between LTCCs and β adrenergic receptors (βARs) within distinct cardiomyocyte microdomains.
- To elucidate the roles of PKA and CaMKII in this functional complex.
- To explore how this complex is disrupted in the context of heart failure.
Main Methods:
- Whole-cell current recordings and western blot analysis were used to assess global signaling between LTCCs and βARs.
- Super-resolution scanning patch-clamp enabled exploration of local coupling between single LTCCs and β1AR or β2AR in different membrane microdomains.
- Analysis included control and failing cardiomyocytes from both rodents and humans, alongside a Caveolin-3-knockout mouse model.
Main Results:
- Local stimulation of β2ARs (<350 nm) in the transverse tubule microdomain increased LTCC open probability (Po) from 0.054±0.003 to 0.092±0.008.
- This β2AR-LTCC coupling was absent in failing cardiomyocytes from rodents and humans.
- Local β1AR stimulation did not alter LTCC Po, though global activation via β1AR increased LTCC current, primarily involving PKA; β2AR-LTCC regulation requires caveolin-3 and CaMKII activation.
Conclusions:
- LTCC activity is regulated by proximity coupling exclusively through β2ARs, not β1ARs, tuning adrenergic responses in healthy hearts.
- This critical β2AR-LTCC coupling is lost in heart failure.
- Restoring this proximity coupling may offer a therapeutic strategy to improve the adrenergic response in failing cardiomyocytes.
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